Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate.

doi:10.1042/BJ20080805

Paper

Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate.

Published Feb 1, 2009 · Ana Paula Pereira da Silva, T. El-Bacha, N. Kyaw

The Biochemical journal

Q1 SJR score

171

Citations

7

Influential Citations

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Abstract

3-BrPA (3-bromopyruvate) is an alkylating agent with anti-tumoral activity on hepatocellular carcinoma. This compound inhibits cellular ATP production owing to its action on glycolysis and oxidative phosphorylation; however, the specific metabolic steps and mechanisms of 3-BrPA action in human hepatocellular carcinomas, particularly its effects on mitochondrial energetics, are poorly understood. In the present study it was found that incubation of HepG2 cells with a low concentration of 3-BrPA for a short period (150 microM for 30 min) significantly affected both glycolysis and mitochondrial respiratory functions. The activity of mitochondrial hexokinase was not inhibited by 150 microM 3-BrPA, but this concentration caused more than 70% inhibition of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and 3-phosphoglycerate kinase activities. Additionally, 3-BrPA treatment significantly impaired lactate production by HepG2 cells, even when glucose was withdrawn from the incubation medium. Oxygen consumption of HepG2 cells supported by either pyruvate/malate or succinate was inhibited when cells were pre-incubated with 3-BrPA in glucose-free medium. On the other hand, when cells were pre-incubated in glucose-supplemented medium, oxygen consumption was affected only when succinate was used as the oxidizable substrate. An increase in oligomycin-independent respiration was observed in HepG2 cells treated with 3-BrPA only when incubated in glucose-supplemented medium, indicating that 3-BrPA induces mitochondrial proton leakage as well as blocking the electron transport system. The activity of succinate dehydrogenase was inhibited by 70% by 3-BrPA treatment. These results suggest that the combined action of 3-BrPA on succinate dehydrogenase and on glycolysis, inhibiting steps downstream of the phosphorylation of glucose, play an important role in HepG2 cell death.

In Vitro Study

Highly Cited

Study Snapshot

3-BrPA inhibits glycolysis and mitochondrial respiratory functions in HepG2 cells, potentially playing a key role in cell death by inhibiting downstream steps of glucose phosphorylation.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate.

References

Citations

Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review.

Targeting metabolic enzymes with inhibitors can alleviate resistance and improve treatment effectiveness in hepatocellular carcinoma.

Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer

Succinate metabolism and the regulation of SDH show potential as therapeutic targets for treating chronic inflammation, ischemia/reperfusion injury, and cancer in hypoxia-related diseases.

Metabolic control analysis as a strategy to identify therapeutic targets, the case of cancer glycolysis

Metabolic control analysis (MCA) can identify therapeutic targets in cancer glycolysis, enabling new strategies to inhibit cancer cell growth.

Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy

A multi-target metabolic approach may offer a promising new option for treating hepatocellular carcinoma (HCC), as current therapies are aggressive and not curative.

3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells

3BP monotherapy effectively suppresses the malignant phenotype of vemurafenib-resistant melanoma cells by disrupting their metabolic and epithelial-mesenchymal profiles.

Glucose Metabolism in Cancer: The Warburg Effect and Beyond

The Warburg effect, observed in 1924, reveals that cancer cells consume glucose and convert it to lactate, providing energy for uncontrolled replication, paving the way for new cancer therapies.

Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy

3-bromopyruvate (3BP) inhibits breast cancer cell glycolysis, disrupts cytoskeleton, and inhibits cell migration, suggesting potential for metastatic breast cancer therapy.

Novel Hydrazone Derivatives of 3‐Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies

3BP derivatives show promising cytotoxic activity and potential for developing orally potent HK II inhibitors for treating various cancers.

Mitochondrial Respiratory Complexes as Targets of Drugs: The PPAR Agonist Example

PPAR ligands cause complex mitochondrial bioenergetic damage, affecting respiratory control ratio, spare respiratory capacity, coupling efficiency, and causing oxidative stress and structural damage to mitochondria.